Suppression of immune responses in collagen-induced arthritis by a rationally designed CD80-binding peptide agent

Mythily Srinivasan, Rajaraman Eri, Susan L. Zunt, Don John Summerlin, David D. Brand, Janice S. Blum

Research output: Contribution to journalArticle

13 Scopus citations

Abstract

Objective. The CD80/CD86-CD28/CD152 costimulatory pathways transmit signals for CD4+ T cell activation and suppression and are critically involved in the pathogenesis of rheumatoid arthritis (RA). A significant number of CD4+ T cells and macrophages in the rheumatoid synovium express elevated levels of CD80, increasing the potential for costimulation in trans of naive T cells. To determine the effect of blockade of this costimulatory axis in RA, we designed novel CD80-binding peptides and evaluated their therapeutic potential in collagen-induced arthritis (CIA), an animal model of RA. Methods. The conserved MYPPPY motif of CD152 adopts a polyproline type II (PPII) helical conformation in the CD80-CD152 complex. The pairing preferences of the critical residues at the CD80-CD152 interface and their propensity to form PPII helices were integrated to design peptides with optimum PPII helical content that selectively block CD80-receptor interactions. The clinical efficacy was tested in DBA/1LacJ mice that were administered the CD80 blocking agents, called CD80-binding competitive antagonist peptides (CD80-CAPs), at the time of immunization with bovine type II collagen or 3 weeks after immunization. Results. A single administration of select CD80-CAPs significantly reduced the clinical, radiologic, and histologic disease severity in CIA. Importantly, administration of CD80-CAPs during activated immune response significantly suppressed disease development by reducing mononuclear cell infiltration in the joints and mediating peripheral deletion of activated CD4+ T cells. Conclusion. A rationally designed CD80-binding peptide both prevents and suppresses CIA, suggesting a potential application in RA. Apoptosis of activated CD4+ T cells following in vivo blockade suggests that the effects of CD80-CAPs may be long-lasting.

Original languageEnglish (US)
Pages (from-to)498-508
Number of pages11
JournalArthritis and Rheumatism
Volume56
Issue number2
DOIs
StatePublished - Feb 1 2007

ASJC Scopus subject areas

  • Immunology and Allergy
  • Rheumatology
  • Immunology
  • Pharmacology (medical)

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